The cells of the cerebral cortex need to be generated in a timely fashion and then migrate to proper positions prior to the development of synaptic connections and functional circuits. Thus, disturbances in the proliferation, migration, or differentiation of cortical cells can lead to cognitive impairments such as those seen in Down syndrome, autism, and other developmental disabilities. The long-term objectives of this project are to identify the various stem and progenitor cells in the embryonic neocortical wall and then to characterize the molecules controlling neuronal and glial cell production from those progenitors during development of the cerebral cortex. In particular, we are studying how the movement of the mitotic spindle apparatus and expression of fate determining molecules combine to allow for the switch between symmetrical and asymmetrical divisions during neocortical neurogenesis. We will study this process using time-lapse multiphoton microscopy, which enables long term visualization of the stem cells in their intact environment. Combining this imaging technology with overexpression of wild-type and dominant negative gene constructs via stem cell transfection will allow us to determine the molecular requirements of stem cell proliferation in a rapid and straightforward manner.